This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The sense of balance is an important way in which we perceive and interact with our environment. The sense of balance and spatial orientation is conveyed by sensory neurons in the semi-circular canals to the brainstem via the vestibulocochlear nerve. The information is then relayed to the Purkinje cells of the cerebellum, which are responsible for the fine control of movement. Degenerative disorders can irreversibly cause the loss of neurons along this pathway. There are currently no effective treatments to prevent or slow the death of neurons. The etiology of this broad group of disorders includes environmental and genetic insults and can occur late in life or during development. While powerful genetic studies have associated mutant alleles with disease phenotypes, the molecular cues that directly initiate neuron death remain uncertain. It is essential to address this knowledge gap so that neuroprotective strategies can be logically defined and rigorously tested in an in vivo model system. We have identified a vestibular disorder in the weeble mutant mouse (wbl) associated with a mutation in inositol polyphosphate 4-phosphatase (Inpp4a). This unique mouse model has common vestibular signs and an early-onset, patterned Purkinje cell degeneration during development. This patterned nature has facilitated our discovery of a candidate neuroprotective modifier gene that we propose to test for its ability to prevent the death of neurons. The long-term goal of our research is to identify the molecular and genetic mechanisms involved in the pathogenesis of degenerative movement and balance disorders in order that improved treatment strategies can be developed.